Modulation of sulfur mustard toxicity by arginine analogues and related nitric oxide synthase inhibitors in vitro.

The modulating effects of a series of arginine analogues and related nitric oxide synthase inhibitors against the toxicity of sulfur mustard (HD) in primary cultures of chick embryo forebrain neurons were examined. In addition to the previously identified protective compounds, D- and L-nitroarginine methyl ester, eight additional arginine analogues were shown to have significant, concentration-dependent protective characteristics against HD toxicity. Of these, L-nitroarginine was the most potent, increasing the LC50 of vehicle-pretreated HD-treated control cultures by approximately 350%. In addition to these protective agents, five compounds related to arginine were also identified that potentiated the toxicity of HD in the neuron cultures in a concentration-dependent manner. This action occurred at concentrations where these chemicals alone exhibited no toxicity. Characterization of the active compounds in this study showed that it was likely that the protective agents, as well as those compounds that potentiated HD toxicity, were exerting their effects at the same biochemical target, but not through the inhibition of nitric oxide synthase. Although the identity of this target site is as yet unknown, these studies demonstrate that subtle alterations to the arginine structure can yield compounds that differentially modulate the toxicity of HD through their activity at a common target site.